A. James Hudspeth, Ph.D., M.D.
"By the time I was five, I was interested in science, especially in learning about living things," James Hudspeth recalls. It is an interest that endures to this day as the central focus of his career.
As children growing up in the rural outskirts of Houston, Texas, Dr. Hudspeth and his younger brother avidly collected just about anything: rocks, fossils, shells, bird nests, and bones. They collected living things, tootheir home became a virtual zoo. "We had more than 200 pets," Dr. Hudspeth boasts. "Dogs, cats, raccoons, opossums, snakesyou name it."
Dr. Hudspeth officially launched his research career at the age of 14, when he went to work part time in the laboratory of Peter Kellawey, a physiologist at Baylor Medical College and a family friend. He continued to work with Kellawey until he graduated from Harvard, where he received his B.S. in biochemistry. Dr. Hudspeth entered graduate school at Harvard Medical School in 1967, where he worked with Torsten Wiesel and David Hubel, Nobel laureates for their pioneering vision research, until 1974, by which time he had earned both his M.D. and his Ph.D. degrees.
Finding a Direction
When his graduate mentors assigned him to deliver a series of lectures to medical students on hearing and related topics, Dr. Hudspeth was "shocked to find that even though hearing has some really remarkable properties, very little was known about itthe critical experiments just hadn't been done." He decided that he could help bridge that gap and, as a postdoctoral fellow at the Karolinska Hospital in Stockholm, began to study the mechanisms of hearing.
Upon his return to the United States, he narrowed his work even further in his studies of the inner ear, which began at the California Institute of Technology. His first challenge was to find a way to study the inner ear outside its well-protected site in the head. His answer lay in the fact that the amphibian ear is structurally similar to the mammalian ear but easier to access.
Discovering How It Works
Vibrations pass from the outside world through a series of bony structures to the cochlea, a coiled tube that senses the various frequencies present and passes this information to the brain. The actual sensors are hair cells, tipped with bundles of fine "feelers" called stereocilia, with taller stereocilia occupying one side and shorter stereocilia occupying the other.
Hair cells populate the length of the cochlea down the basilar membrane. High frequencies penetrate only a short way into the cochlea and vibrate the basilar membrane toward the outside end; lower tones vibrate the basilar membrane further in. Pitch perception is thus encoded in the position along the basilar membrane of the hair cells that are the most strongly stimulated.
Developing New Techniques and Findings
Dr. Hudspeth developed methods to remove living hair cells from frogs and record the electrical changes that occur when their stereocilia are tickled with a vibrating probe. The new technique enabled Dr. Hudspeth and his research team to confirm that the stereocilia are in fact the hair cell's sensory organelles.
They also found that displacing the stereocilia, even by the diameter of an atom, causes a change in voltage in the hair cell. This change is the result of ions passing through membrane porescalled ion channelsthat open in response to displacement. They found that this response was incredibly fastthe channels open only a few microseconds after the stereocilia move to one side.
Still, the molecular mechanism that opened the ion channels remained unclear to researchers. The speed and sensitivity of the response, according to Dr. Hudspeth, indicated that there must be a mechanical link between the ciliary movement and the channel opening. He called this link a "gating spring," but what such a spring might look like and how it might work remained a mystery. "There had to be a physical process going on," Dr. Hudspeth remembers thinking.
Unraveling the Mystery
While Dr. Hudspeth and his team were struggling with their research dilemma, another researcherelectron microscopist James Pickles in the United Kingdomwas making headway in his work. In 1984, he observed exquisitely thin filaments linking the taller stereocilia to the tips of their shorter neighbors. The geometry was such that deflection of the bundle toward the taller member would tighten the filament, while deflection in the opposite direction would relieve the tension.
Subsequently, Dr. Hudspeth and others were able to demonstrate that the "tip links" were intimately involved in hair-cell action, in part by observing that disruption of the links resulted in a loss of sensitivity to displacement.
Dr. Hudspeth presumed that the linking filament is tied to a "trap door" on the cilium's ion channel protein and pulls it open when displacement causes filament tension to increase. Although this theory is not yet completely proved, it is consistent with the evidence and represents a new mechanism by which an ion channel's opening and closing can be regulated.
After several years at the University of California at San Francisco and at the University of Texas Southwestern Medical School, where he founded a neuroscience program and chaired the department of cell biology, Dr. Hudspeth moved to The Rockefeller University in 1995.
He is currently engaged in several projects designed to further illuminate hair-cell function. One of these projects entails a search for genes that encode the various proteins involved in the hair cell's responsiveness. Another involves an exploration of the mechanism by which hair cells adjust their sensitivity in response to their exposure to constant noise.
In the course of this study, Dr. Hudspeth has concluded that the hair-cell ion channels spontaneously close after the cilia are deflected for as little as 0.1 second. It seems that at the point at which the tip link attaches to the longer stereocilium, a motor protein slides downward, readjusting the tension. This readjustment likely relies on a motor protein called myosinthe same protein responsible for muscle movement.
The Amplification Mechanism: A Goal for Future Research
Today, Dr. Hudspeth is focusing his efforts on identifying a poorly understood amplification mechanism that appears to be at work in the cochlea. "The ear is about 100 times more sensitive than we can explain," he says. "If you put a microphone in it, you can detect noises that the ear itself generates." These sounds may be related to the amplification mechanism. Myosin molecules might be involved in this system as well.
The sound you hear is Dr. Hudspethsingle-mindedly working toward an answer.
© 2013 Howard Hughes Medical Institute. A philanthropy serving society through biomedical research and science education.